chr11-74835963-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001098638.2(RNF169):ā€‹c.1360T>Gā€‹(p.Ser454Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 32)
Exomes š‘“: 0.000022 ( 0 hom. )

Consequence

RNF169
NM_001098638.2 missense

Scores

3
5
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.48
Variant links:
Genes affected
RNF169 (HGNC:26961): (ring finger protein 169) Enables K63-linked polyubiquitin modification-dependent protein binding activity and nucleosome binding activity. Involved in cellular response to DNA damage stimulus and negative regulation of double-strand break repair. Located in cytosol; nuclear lumen; and site of double-strand break. [provided by Alliance of Genome Resources, Apr 2022]
XRRA1 (HGNC:18868): (X-ray radiation resistance associated 1) Involved in response to X-ray. Located in cytoplasm and nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RNF169NM_001098638.2 linkuse as main transcriptc.1360T>G p.Ser454Ala missense_variant 6/6 ENST00000299563.5
RNF169XM_011544889.4 linkuse as main transcriptc.1423T>G p.Ser475Ala missense_variant 6/6
RNF169XM_047426707.1 linkuse as main transcriptc.694T>G p.Ser232Ala missense_variant 6/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RNF169ENST00000299563.5 linkuse as main transcriptc.1360T>G p.Ser454Ala missense_variant 6/61 NM_001098638.2 P1
XRRA1ENST00000530562.5 linkuse as main transcriptc.*65+7387A>C intron_variant, NMD_transcript_variant 2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152164
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
249434
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135362
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000464
Gnomad NFE exome
AF:
0.0000265
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000219
AC:
32
AN:
1461872
Hom.:
0
Cov.:
33
AF XY:
0.0000220
AC XY:
16
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000562
Gnomad4 NFE exome
AF:
0.0000261
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152164
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.00000828
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 15, 2024The c.1360T>G (p.S454A) alteration is located in exon 6 (coding exon 6) of the RNF169 gene. This alteration results from a T to G substitution at nucleotide position 1360, causing the serine (S) at amino acid position 454 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.076
T
BayesDel_noAF
Benign
-0.28
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.096
T
Eigen
Uncertain
0.68
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.71
T
M_CAP
Benign
0.012
T
MetaRNN
Uncertain
0.57
D
MetaSVM
Benign
-0.64
T
MutationAssessor
Uncertain
2.1
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-1.0
N
REVEL
Benign
0.20
Sift
Benign
0.040
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.99
D
Vest4
0.53
MutPred
0.44
Loss of phosphorylation at S454 (P = 0.0476);
MVP
0.64
MPC
0.71
ClinPred
0.33
T
GERP RS
6.0
Varity_R
0.11
gMVP
0.30

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs746047345; hg19: chr11-74547008; API